Reviews by Elvevg and Weinberger (Cognitive Neuropsychiatry, 2009) and Dickinson and Elvevg (Neuroscience, 2009) explored 1) how the catechol-O-methyltransferase (COMT) polymorphism valine158methionine (val/met) has helped to characterize various interacting aspects of complexity with relation to genes and cognition;2) how COMT val/met has been used to develop and validate behavioral and neurophysiological phenotypes;3) COMT as a tool for delineating overlapping neural functional systems;4) gene-gene and gene-environmental interactions;and 5) gene effects of COMT on cognition regulated by environmental, demographic and developmental influences. COMT can be viewed as a model to understand how a single functional polymorphism can have a dramatic effect on individual differences. Dopamine is modulated through many genes and thus affects prefrontal cortical functioning. One of these genes, COMT, has been shown to affect many cognitive processes that are dependent on the prefrontal cortex. Dopamine has been implicated in the pathogenesis of a number of psychiatric disorders (i.e. schizophrenia, bipolar disorder, depression) and as a pharmacological target. The clinical benefit of antipsychotic medications blocking D2 receptors either pre-synaptically or post-synaptically is a logical foundation for the underlying mechanisms for the presentation of psychosis as evidenced by more D2 receptors and increased levels of dopamine found in patients with schizophrenia. Dopamine is a major neurotransmitter used in higher order behavioral and cognitive functions with its quantity in the prefrontal cortex modulating many core cognitive processes. There are many factors regulating dopamine levels, only one being COMT. COMT is an enzyme that degrades cortical dopamine, thereby influencing dopamine levels. A substitution of val by met in the peptide sequence impacts enzyme stability and reduces COMT enzyme activity by more than half. Thus, the val allele is more stable and leads to greater dopamine degradation. The converse is true for the met allele which has a less stable COMT enzyme resulting in more dopamine in the prefrontal cortex. Furthermore, a growing body of research shows a well established association of COMT val158mt variation with dopamine modulation of prefrontal physiology and information processing. The polymorphism serves as a place for refinements to behavioral and neurophysiological phenotypes, as a tool for delineating overlapping neural systems and within-gene and between-gene interactions, and as a model for the complexity of understanding gene effects on cognition in varying environments, and demographic and developmental influences. An enormous amount of detail remains to be discovered about schizophrenia susceptibility genes, their regulatory function, how they interact and their effect on brain systems. There is a new strategy of using genetic phenotype associations to examine neurobiological hypotheses in both healthy and impaired brain function, which requires the development, validation and use of novel behavioral and neurophysiological phenotypes to unravel the pathologies within neural functional systems. Other approaches being considered are intra-individual variability, mapping functional networks, systems and patterns of cortical functional connectivity, or adding a dimension of real-time to chart the fine-grained temporal nature of neural systems and their interaction, taking into account that dopamine functions dynamically. We will continue work in this area, as there is still much to uncover about the association between genes and cognition, and the application of this knowledge in the field of behavioral medicine and treatments for schizophrenia.